Many obstacles stand in the way of fully harnessing hippocampal neurogenesis for the treatment of mental illness and other brain disorders. One of the most glaring knowledge gaps is the lack of understanding about differences between rodent and human neurogenesis. More specifically, almost nothing is known about human neurogenesis except that it persists into adulthood (Eriksson et al., 1998
; Manganas et al., 2007
). More information is needed on the extent of neurogenesis, the function of adult-generated neurons, the location and function of the adult stem cell, and even whether the stages of neurogenesis that are so well-characterized in the rodent are recapitulated in the human. We need to understand these fundamental concepts before we can fully appreciate how these dependent measures are changed in mental illness. For example, the recent pioneering study in human MDD patients examined the number of dividing Ki-67- and nestin-expressing cells (Boldrini et al., 2009
). However, it remains to be proven in the human and even in the rodent brain whether nestin expression is a sufficient requirement to label the stem cells. We also need better understanding of how new neurons integrate into hippocampal circuitry. To this end, more functional approaches combined with computational modeling may provide critical insight (Gradin and Pomi, 2008
). A more thorough examination of human post-mortem samples is also desperately needed to better understand human neurogenesis and how it is similar to, and distinct from, rodent neurogenesis.
On a related note, more work is needed on precisely what other neurogenic niches exist in the basal (Cameron and Dayer, 2008
; Gould, 2007
) or injured brain (Magavi and Macklis, 2002
). Such information in the rat or mouse brain but especially in the human brain would be immensely useful for understanding the etiology of mental illnesses as well as delineating treatment options and limitations. The importance of the niche reminds us that while in vitro
work will remain invaluable for the mechanistic insight it can provide to us about adult hippocampal neurogenesis, it is necessary to pursue as much work in vivo
or in situ
as possible. In fact, there is growing appreciation that while “stem cell genes” have been identified, the concept of “stemness” in fact may rely solely on the niche in which the cell develops (Lander, 2009
). Powerful new tools for imaging new neurons in the living brain are likely to help bridge this knowledge gap (Manganas et al., 2007
; Pereira et al., 2007
), and such data would bring us closer to being able to direct new neurons to places of primary pathology in each disease, and to design approaches to specifically target select stages of neurogenesis.
It is also critical to improve our fundamental understanding of mental illnesses and their pharmacological treatments (Dhikav and Anand, 2007
), and to parlay key aspects of the disorders into common use in basic animal models. For example, one key assessment lacking in the MDD and PTSD literature is whether there is a heterogeneous response of neurogenesis to stress, though a heterogeneous behavioral response has been described (Krishnan et al., 2007
). Given the differences in allostatic load according to experience (McEwen, 2007
), examination of whether neurogenesis is correlated with – or perhaps causative to – the development of individual susceptibility or resilience to stress is a high priority for the field.
A more complete understanding of disease pathophysiology and neuromechanisms of effective treatments will also require additional and more complete model systems. For example, the prairie vole has a well-delineated social structure and can provide an excellent model for depression, anxiety, social isolation, and perhaps even PTSD (e.g. Grippo et al., 2008
). Also, recently-developed mouse models to track and inducibly manipulate stem cells and their progeny need to be incorporated with existing disease models to greatly advance our understanding of the complex interplay between disease models and neurogenesis (Lagace et al., 2007b
; Mori et al., 2006
). Even more commonly-used approaches to suppress hippocampal neurogenesis, like cranial irradiation, are proving very useful in uncovering novel roles for adult neurogenesis in psychiatric disorders like addiction (Noonan et al., in press
). Perhaps using such approaches more widely and rigorously will allow us to learn more about how we might encourage migration of SGZ-generated neurons into nearby regions, as has been shown in other brain regions (Yamashita et al., 2006
). This would potentially allow directed migration of adult-generated neurons to the site of pathology in each brain disorder, vastly enhancing the utility of this approach for translational use.
Another critical obstacle to address is the differences in incidence and treatment of mental disorders by sex. It is clear that sex steroids exert potent influences on the dentate gyrus physiology and in stress responses (Goel and Bale, 2009
; Hajszan et al., 2007
). For example, sex appears to play a critical role in mental disorders and in regulation of neurogenesis in the rat and human (Boldrini et al., 2009
; Galea, 2008
). As the mouse is a major model species in neuroscience, it is notable that evidence for sex differences in the mouse remains inconclusive (Lagace et al., 2007a
; Sakata et al., 2009
; Silasi et al., 2004
). Given the demonstrated implications that phytoestrogens have on laboratory animal and human cognition and behavior (e.g. Lephart et al., 2002
; Patisaul and Polston, 2008
), it will be critical for future preclinical studies to account for phytoestrogens in laboratory animal chow as this will make translational application of the data more feasible.
While many of the obstacles noted above relate to human neurogenesis and translational efforts, one final obstacle falls squarely in the realm of the basic researchers. We also need a more complete understanding the function of adult-generated neurons, and the dentate gyrus as a whole. This likely will emerge as researchers employ better models of inducible and reversible ablation of neurogenesis (e.g. Dupret et al., 2008
; Saxe et al., 2006
; Singer et al., 2009
), and as cleaner and more sophisticated ways to assess hippocampal function in behavioral tasks are developed.